Changes in the oral mucosa leading to epithelial thickening in response, for example, to tooth brushing represent functional adaptations of structure. Similar changes seen in lesions such as leukoplakia and epidermoid carcinoma are non-functional and represent derangement of normal homeostatic control mechanisms. Balanced rates of cell death and cell proliferation are necessary for homeostasis. In experimental hyperplasia, linked changes in rates of mitosis and of cellular synthesis for function have been found. Methods for assessing overall rates of epithelial metabolism have been developed by examining rates of in vitro utilization of labelling glucose, amino acids, fatty acids, uridine and thymidine by pure epithelial sheets produced from either hamster cheek pouch or ear using EDTA. Detection of a mitosis-related diurnal variation in metabolic activity and comparable rates of uptake of 14C amino acids by in vivo and in vitro techniques indicate the validity of the method. To investigate the mechanisms by which epithelial hyperplasia is induced in oral mucosa and epidermis the in vitro assay systems for metabolism and cell proliferation will be used to 1) determine the time course and dose response curves of metabolic and proliferative changes in podophyllin, hexadecane tetradecanoyl phorbol acetate (TPA), 2) determine the site of action of the above agents using pure epithelial sheets or intact tissue in vitro, and 3) investigate possible mechanisms of action of the agents by the use of specific pharmacologic agents.